Abstract/ProjectSummary Thisproposaldescribesatwoyearintegratedmentoredtrainingprogramfollowedbyathreeyearindependent programforthedevelopmentofanacademicbasicscienceresearchcareeringastroenterology.ThePIhas completed her Ph.D. in Cell Biology and seeks to build on her existing research experience and skills to becomeasuccessfulindependentinvestigatorinanareaofresearchthatrequiresadditionalessentialmulti disciplinary training. The PI will acquire unique skills set to study the role of the key inflammatory mediator IKK? in the regulation of the esophageal microenvironment. While activation of cytokines, chemokines, and inflammatory mediators has been identified in esophageal diseases, little information is available about the molecular mechanisms of this activation in these diseases. To dissect the relevant pathways, the PI will integrateconceptsfromimmunologyandthetumormicroenvironmentthroughformalcoursework,masteringof relevanttechnicalskills,andmentorshipbyexpertsinthesefields.Thecandidate?sMentor,Dr.JonathanKatz, isanexpertingeneticallyengineeredmousemodelsofdiseaseandesophagealsquamouscellbiology.The candidate?sCoMentors,Dr.AnilRustgiandDr.SandraRyeom,provideadditionalexpertiseintranscriptional regulation, signal transduction, threedimensional culture, angiogenesis, and the regulation of the microenvironment. A superb advisory committee composed of leading NIHfunded investigators with broad expertise has been formed to provide scientific and professional guidance. Here, we will take advantage of newmousemodelsandcomplementaryinvitrosystemsutilizing3Dculturesystemtotestthehypothesisthat activationoftheIKK?pathwaywithinesophagealepithelialcellsproducesamicroenvironmentthatpotentiates esophageal dysplasia, cancer, and other diseases. To explore these processes, we will undertake three interrelated Specific Aims. In Aim 1 (K99 phase), we will define the role of epithelial IKK? signaling in the microenvironmentandinepithelialendothelialcellinteractionsintheesophagus.Thiswillbeundertakenusing a novel transgenic mouse model and primary esophageal epithelial cells in a 3D tissue context. In Aim 2 (K99/R00 phases), we will determine the requirement for epithelial IKK? signaling in limiting expansion of esophageal stromal myofibroblasts. Here, we will utilize esophagealspecific IKK? knockout mice and 3D culture.InAim3(R00phase),wewilldeterminethefunctionalinterplayofSTAT3activationandIKK?/NF?B signaling in the inflammatory response of esophageal epithelial cells. To examine these interactions, we will employIKK?knockinmicethatarecrossedwithSTAT3floxedmice.Theproposedresearchwillbesupported bythesuperbandcollegialintellectualenvironmentaswellastheexceptionalresourcesandfacilitiesavailable tothePI.Weanticipatethatthesestudieswillprovideinsightintothefactorsthatregulatenormalesophageal epithelial homeostasis, the microenvironment, and the pathways that are disrupted in esophageal diseases, bothbenignandmalignant.